NMDA receptor activity produces synaptic plasticity in the central nervous system that affects processes for learning and memory, including long-term potentiation and long-term depression (Dingledine R., Crit. Rev. Neurobiol., 4(1):1–96, 1988). However, prolonged activation of NMDA receptor under pathological conditions (such as cerebral ischaemia and traumatic injury) causes neuronal cell death (Rothman S. M. and Olney J. W., Trends Neurosci., 18(2):57–8, 1995). NMDA receptor-mediated excitotoxicity may contribute to the etiology or progression of several neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Since open channel blockers of NMDA receptors were shown, in the late 1980s, to have potential for therapy of ischemic stroke, the receptor has been considered an attractive therapeutic target for the development of neuroprotective agents. Unfortunately, the development of these compounds as neuroprotectants is often limited by their psychiatric side-effects associated with their undesired pharmacodynamic properties such as slow dissociation from the receptor (Muir K. W. and Lees K. R., Stroke, 26(3):503–13, 1995).
The advent of combinatorial chemistry technology in recent years has greatly facilitated the process of drug discovery. For example, a set of arginine-rich hexapeptides, which potently blocked NMDA receptor, have recently been identified from a peptide combinatorial library (Ferrer-Montiel A. V., et al., Nat. Biotechnol., 16(3):286–91, 1998). However, development of peptides as drugs is often hampered by their lack of oral bioavailability due to enzymatic degradation before entry into systemic circulation.